The n e w e ng l a n d j o u r na l of
clinical practice
From the Division of Infectious Diseases,
Children’s Hospital Boston and Harvard
Medical School, Boston. Address reprint
requests to Dr. Wessels at the Division of
Infectious Diseases, Children’s Hospital
Boston, 300 Longwood Ave., Boston, MA
02115, or at michael.wessels@childrens
.harvard.edu.
N Engl J Med 2011;364:648-55.
Copyright © 2011 Massachusetts Medical Society.
An audio version
of this article
is available at
NEJM.org
648
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m e dic i n e
Streptococcal Pharyngitis
Michael R. Wessels, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the author’s clinical recommendations.
A 10-year-old girl presents with a sore throat and fever that has lasted for 1 day. She
appears flushed and moderately ill. Physical examination reveals a temperature of
39°C, tender bilateral anterior cervical lymph nodes that are 1 to 2 cm in the greatest
dimension, and erythema and whitish-yellow exudate over enlarged tonsils and the
posterior pharynx. A rapid antigen-detection test from a throat-swab specimen is
positive for group A streptococcus. How should the patient be evaluated and treated?
The Cl inic a l Probl em
Sore throat is an extremely common presenting symptom. Acute pharyngitis accounts
for 1.3% of outpatient visits to health care providers in the United States, and it ac­
counted for an estimated 15 million patient visits in 2006.1 Group A streptococcus
(Streptococcus pyogenes) is responsible for 5 to 15% of cases of pharyngitis in adults and
20 to 30% of cases in children.2 Streptococcal pharyngitis occurs most commonly
among children between 5 and 15 years of age. In temperate climates, the incidence
is highest in winter and early spring. The economic burden of streptococcal pharyn­
gitis among children in the United States has been estimated at $224 million to
$539 million per year, with a substantial fraction of the associated costs attribut­
able to parents’ lost time from work.3
Streptococcal pharyngeal infection not only causes acute illness but also can trig­
ger the postinfectious syndromes of poststreptococcal glomerulonephritis and acute
rheumatic fever. Rheumatic fever is currently uncommon in most developed countries,
but it remains the leading cause of acquired heart disease among children in many
resource-poor areas such as sub-Saharan Africa, India, and parts of Australasia.4
S t r ategie s a nd E v idence
Evaluation
The onset of symptoms in patients with streptococcal pharyngitis is often abrupt.
In addition to throat pain, symptoms may include fever, chills, malaise, headache,
and particularly in younger children abdominal pain, nausea, and vomiting.5 Oc­
casionally, streptococcal pharyngitis is accompanied by scarlet fever, which is man­
ifested as a finely papular erythematous rash that spares the face, may be accentuated
in skin folds, and may desquamate during convalescence. Cough, coryza, and con­
junctivitis are not typical symptoms of streptococcal pharyngitis, and, if present,
they suggest an alternative cause such as a viral infection. Throat pain may be severe,
and it is often worse on one side. However, severe unilateral pain or an inability to
swallow should raise concern about a local suppurative complication such as periton­
sillar or retropharyngeal abscess, particularly if these symptoms arise or progress
several days into the illness. Among children younger than 3 years of age, exudative
pharyngitis due to streptococcal infection is rare. In this age group, streptococcal
n engl j med 364;7  nejm.org  february 17, 2011
The New England Journal of Medicine
 clinical pr actice

infection may be manifested as coryza, excoriat­

Table 1. Infectious Causes of Acute Pharyngitis.
ed nares, and generalized adenopathy.5 In most
persons, fever resolves within 3 to 5 days, and Organism Clinical Manifestations
throat pain resolves within 1 week, even without Viruses
specific treatment.6,7
Rhinovirus Common cold
The diagnosis of streptococcal pharyngitis on
Coronavirus Common cold
clinical grounds is notoriously unreliable.8,9 Symp­
toms and signs are variable, and the severity of Adenovirus Pharyngoconjunctival fever
illness ranges from mild throat discomfort alone Influenza virus Influenza
to classic exudative pharyngitis with high fever Parainfluenza virus Cold, croup
and prostration. The diagnosis is further compli­ Coxsackievirus Herpangina, hand–foot–mouth disease
cated by the fact that infection due to many other Herpes simplex virus Gingivostomatitis (primary infection)
agents may be indistinguishable clinically from
Epstein–Barr virus Infectious mononucleosis
streptococcal pharyngitis (Table 1).
Cytomegalovirus Mononucleosis-like syndrome
Clinical scoring systems have been developed to
predict the likelihood of streptococcal infection Human immunodeficiency virus Acute (primary) infection syndrome
among children and adults presenting with sore Bacteria
throat. These systems are based on assessment for Group A streptococci Pharyngitis, scarlet fever
suggestive clinical findings: fever, tonsillar swell­ Group C and group G streptococci Pharyngitis
ing or exudate, tender and enlarged anterior cer­
Mixed anaerobes Vincent’s angina (necrotizing gingivo-
vical lymph nodes, and the absence of cough. The stomatitis)
probability of positive results of a throat culture Fusobacterium necrophorum Lemierre’s syndrome (septic thrombo-
or a rapid antigen-detection test ranges from 3% or phlebitis of the internal jugular vein)
less in patients with no suggestive clinical crite­ Arcanobacterium haemolyticum Pharyngitis, scarlatiniform rash
ria to approximately 30 to 50% in those with all Neisseria gonorrhoeae Pharyngitis
of them8,10-12 (Table 2). Clinical prediction rules
Treponema pallidum Secondary syphilis
based on these criteria have been validated in both
adults and children to help identify patients in Francisella tularensis Pharyngeal tularemia
whom evaluation with a throat culture or rapid Corynebacterium diphtheriae Diphtheria
antigen-detection test is warranted.10 For exam­ Yersinia enterocolitica Pharyngitis, enterocolitis
ple, in the absence of particular risk factors, such Yersinia pestis Plague
as known exposure to a person with streptococcal Mycoplasma pneumoniae Bronchitis, pneumonia
pharyngitis or a history of acute rheumatic fever
Chlamydophila pneumoniae Bronchitis, pneumonia
or rheumatic heart disease, a throat culture or
Chlamydophila psittaci Psittacosis
rapid antigen-detection test would not be indicated
in a patient meeting only one or none of the
criteria listed above.
Another consideration in deciding whether to Laboratory Tests
perform a throat culture or rapid antigen-detection Because the presentation is nonspecific, the di­
test is the fact that certain persons are asymptom­ agnosis of streptococcal pharyngitis should be
atic carriers of S. pyogenes. The organism can be based on the results of a specific test to detect
cultured from the pharynx in the absence of symp­ the presence of the organism: a throat culture or
toms or signs of infection during winter months a rapid antigen-detection test of a throat-swab
in approximately 10% of school-age children and specimen. Swabbing the posterior pharynx and
less frequently in persons in other age groups. tonsils and not the tongue, lips, or buccal mu­
Carriage can persist for weeks or months and is cosa increases the sensitivity of both the culture
associated with a very low risk of suppurative or and rapid antigen-detection test.15 Measurement
nonsuppurative sequelae or of transmission to of serum antibodies to streptolysin O or DNase B,
others. Therefore, in the absence of suggestive although useful for retrospective diagnosis of
clinical findings, a positive culture or rapid anti­ streptococcal infection to provide support for the
gen-detection test is likely to reflect incidental diagnosis of acute rheumatic fever or poststrep­
carriage of S. pyogenes.13,14 tococcal glomerulonephritis, is not helpful in the

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 The n e w e ng l a n d j o u r na l of m e dic i n e

question is whether it is worthwhile to pursue di­

Table 2. Clinical Scoring System and Likelihood
of Positive Throat Culture for Group A Streptococcal agnostic testing and to offer antibiotic treatment
Pharyngitis.* for suspected or confirmed cases. Although post­
streptococcal glomerulonephritis does not appear
Criteria Points†
to be prevented by antibiotic treatment of strepto­
Fever (temperature >38°C) 1 coccal pharyngitis, several other potential bene­
Absence of cough 1 fits have been suggested to justify treatment.
Swollen, tender anterior cervical nodes 1 Studies largely involving military recruits in
Tonsillar swelling or exudate 1 the 1950s have shown that antibiotic treatment
Age
reduces the risk of subsequent development of
acute rheumatic fever.7,19-21 In general, these trials
3 to <15 yr 1
involved study-drug assignment based on military
15 to <45 yr 0
record number (rather than true randomization)
≥45 yr −1 and were not consistently placebo-controlled, nor
were they fully blinded. Despite these limitations,
* The information is adapted from McIsaac et al.10
† A score of 0 or a negative score is associated with a risk a meta-analysis that included nine such studies
of 1 to 2.5%, 1 point is associated with a risk of 5 to (involving 6702 patients) showed that administra­
10%, 2 points is associated with a risk of 11 to 17%, tion of various regimens of intramuscular peni­
3 points is associated with a risk of 28 to 35%, and
4 or more points is associated with a risk of 51 to 53%. cillin was associated with an 80% reduction in the
incidence of acute rheumatic fever, as compared
with no antibiotic treatment (relative risk, 0.20;
management of pharyngitis, since titers do not 95% confidence interval [CI], 0.11 to 0.36).22
begin to increase until 7 to 14 days after the onset Antibiotic therapy also reduces the risk of sup­
of infection, reaching a peak in 3 to 4 weeks. purative complications of streptococcal infection.
Because the results of throat cultures are not A Cochrane review of randomized, placebo-con­
available for 1 or 2 days, rapid antigen-detection trolled trials showed that antibiotic therapy sig­
tests have been developed to detect S. pyogenes di­ nificantly reduced the risks of acute otitis media
rectly from throat swabs, generally within min­ (in 11 studies; relative risk, 0.30; 95% CI, 0.15 to
utes.16 These tests are based on acid extraction of 0.58) and peritonsillar abscess (in 8 studies; rela­
cell-wall carbohydrate antigen and detection of tive risk, 0.15; 95% CI, 0.05 to 0.47).23
the antigen with the use of a specific antibody. Without treatment, streptococcal pharyngitis
An alternative approach has been the rapid iden­ is associated with persistence of positive throat
tification of S. pyogenes–specific DNA sequences cultures for up to 6 weeks in 50% of patients.24
by means of hybridization with a DNA probe or In contrast, treatment with an active antibiotic
by means of a real-time polymerase-chain-reac­ results in negative throat cultures within 24 hours
tion assay. A wide range of sensitivity (generally, in more than 80% of patients.25,26 It is recom­
70 to 90%) has been reported for currently avail­ mended that children receive treatment for strep­
able rapid antigen-detection tests, and the mea­ tococcal pharyngitis for 24 hours before they
sured sensitivity has been shown to depend on the return to school because shorter intervals are as­
clinical likelihood of streptococcal infection in sociated with a higher rate of positive cultures.27
the test population.17,18 The specificity of rapid Antibiotic therapy also reduces the duration of
antigen-detection tests is 95% or greater, and thus streptococcal symptoms. In controlled trials, the
a positive result can be considered to be definitive rates of fever and sore throat were significantly
and to obviate the need for culture. A rapid lower at 24 hours among patients treated with
antigen-detection test is less sensitive than cul­ antibiotics than among patients who received pla­
ture, so most guidelines recommend obtaining a cebo.6,7,25,26 Antibiotics may be less effective in
throat culture if the rapid antigen-detection test ameliorating symptoms if treatment is delayed.6
is negative.
Approaches to Diagnosis and Treatment
Rationale for Antibiotic Treatment In the 1950s and 1960s, the most compelling
Since streptococcal pharyngitis is a self-limited reason for antibiotic treatment of streptococcal
illness in the vast majority of cases, a reasonable pharyn­gitis was to prevent acute rheumatic fever.

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 clinical pr actice
Although high rates persist in several areas of the
world, the incidence of acute rheumatic fever in
developed countries has declined dramatically,
raising questions regarding whether the tradition­
al approach to the diagnosis and treatment of
streptococcal pharyngitis is still appropriate in
such settings.28
In this context, several decision analyses have
compared the cost-effectiveness of various strate­
gies for diagnosis and treatment. These strategies
include antibiotic treatment based on the results
of a throat culture, no treatment, treatment of all
patients with symptoms, treatment based on the
results of a rapid antigen-detection test alone,
treatment based on the results of a rapid antigen-
detection test plus culture in patients with a nega­
tive rapid antigen-detection test, and treatment
based on an algorithm of signs and symptoms
alone or in combination with the selective use of
culture, rapid antigen-detection test, or both. One
analysis of four strategies for the management of
pharyngitis in children (treatment of all patients
with symptoms, rapid antigen-detection test alone,
culture alone, or rapid antigen-detection test plus
culture) concluded that a rapid antigen-detection
test plus culture was most cost-effective when the
costs of managing complications of streptococcal
infection and treatment were included.29 In this
analysis, a relatively low sensitivity value (55%) was
assigned to the rapid antigen-detection test, and
the marginal benefit of culture decreased with
increasing sensitivity of the rapid antigen-detec­
tion test. Another study involving children,
which included these four strategies plus a “treat
none” strategy and used a sensitivity of 80% for
the rapid antigen-detection test, showed that
the rapid antigen-detection test alone was the
most cost-effective approach.30 A similar study
involving adults concluded that empirical treat­
ment of all symptomatic patients was the least
cost-effective strategy and that the other four
strategies had similar cost-effectiveness. The
strategy of treating only patients with a positive
culture was the least expensive. However, a
rapid antigen-detection test plus culture would
be the most cost-effective strategy if the preva­
lence of streptococcal pharyngitis were greater
than 20%.31 A consistent finding is that empiri­
cal antibiotic treatment on the basis of symptoms
alone results in overuse of antibiotics, increased
costs, and an increased rate of side effects from
antibiotics, as compared with other strategies.
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Treatment Regimens
Recommended treatment regimens are summa­
rized in Table 3.
Follow-up after Treatment
Repeat culture is not generally recommended after
treatment for uncomplicated streptococcal pharyn­
gitis. A positive culture after appropriate treatment
is of uncertain clinical significance if symptoms
and signs of pharyngitis have resolved. Although
such a result could imply failure of treatment, it
also may mean that the patient is a streptococcal
carrier who had an intercurrent episode of phar­
yngitis caused by another organism.
A rapid antigen-detection test, culture, or both
should be performed if symptomatic pharyngitis
recurs after treatment; if the result is positive, re­
treatment is indicated. If incomplete adherence to
the initial regimen is a concern, intramuscular
benzathine penicillin may be preferred for retreat­
ment. Recurrence may also result from reinfec­
tion from a household contact who is a carrier.
Although carriage is not an indication for treat­
ment in most circumstances, many experts rec­
ommend cultures of throat-swab specimens from
household contacts and treatment of all carriers if
reinfection is suspected. Clindamycin and cepha­
losporins appear to be more effective than peni­
cillin in eradicating carriage, and either of these
agents is preferred in this situation.39,40 S. pyogenes
can persist for days on toothbrushes, but a role
in reinfection has not been proved. There is no
convincing evidence that household pets are a
source of recurrent streptococcal infection.
A r e a s of Uncer ta in t y
Several articles have suggested that bacteriologic
cure rates associated with penicillin treatment of
streptococcal pharyngitis have decreased in recent
decades and that cephalosporins are more effica­
cious.41,42 A meta-analysis of 51 studies showed
no significant difference in the bacteriologic fail­
ure rate associated with penicillin treatment be­
tween the period from 1953 to 1979 and the period
from 1980 to 1993 (10.5% and 12%, respectively).43
A later meta-analysis of 35 comparative trials
from 1970 through 1999, involving 7125 chil­
dren, showed a small, but significant difference
in the bacterial cure rate favoring cephalosporins
over penicillin.41 However, as in the earlier study,
there was no significant change in the cure rate
651
 652
Table 3. Recommended Treatment Regimens for Group A Streptococcal Pharyngitis.*

Drug Dose, Route, and Duration Comments Reference

Penicillin V Patient weight <27 kg: 250 mg orally two or three times a day
for 10 days; patient weight ≥27 kg: 500 mg two or three
times a day for 10 days
Benzathine penicillin G Patient weight <27 kg: 600,000 units intramuscularly as a
single dose; patient weight ≥27 kg: 1.2 million units
intramuscularly as a single dose
Amoxicillin 20 mg/kg/dose orally twice a day to maximum of 500 mg/dose
for 10 days or 50 mg/kg orally once a day to maximum
of 1 g once a day for 10 days
Narrow spectrum, inexpensive, vast clinical experience
Best evidence for prevention of acute rheumatic fever;
obviates concerns about patient adherence
Oral suspension more palatable than penicillin; the only FDA- Clegg et al.,32 Lennon et al.33
approved once-daily regimen (Moxatag, MiddleBrook
Pharmaceuticals) is a timed-release formulation for
The

patients ≥12 yr, 775 mg orally once a day for 10 days; al-
though not FDA-approved, standard-formulation amoxicil-
lin once daily has efficacy in children and adults similar to
that of twice-daily amoxicillin or various penicillin
regimens
Alternatives for patients
with penicillin allergy
Cephalexin 20 mg/kg/dose orally twice a day to maximum of 500 mg/dose Cephalosporins considered acceptable alternative for patients
for 10 days who do not have a history of immediate hypersensitivity to
penicillin; first-generation cephalosporins are preferred be-
Cefadroxil 30 mg/kg orally once a day to maximum of 1 g once a day for
cause of narrower spectrum and lower cost†
10 days
Azithromycin 12 mg/kg orally once a day to maximum of 500 mg/dose for FDA-approved for 5-day treatment course; lower doses associ- Liu et al.,35 Tamayo et al.,36
n e w e ng l a n d j o u r na l

The New England Journal of Medicine

5 days ated with higher failure rate among children; resistance Tanz et al.37
of

<8% in most areas of North America but higher in certain

communities and >20% in parts of Europe and Asia‡
Clindamycin 7 mg/kg/dose orally three times a day to maximum of Oral suspension has unpleasant taste; may be associated with Tamayo et al.,36 Tanz et al.,37

n engl j med 364;7  nejm.org  february 17, 2011

300 mg/dose for 10 days higher incidence of Clostridium difficile colitis; resistance Kim and Yong Lee38
<2% in United States and Canada but up to 20% in some

Copyright © 2011 Massachusetts Medical Society. All rights reserved.

m e dic i n e

other countries

* FDA denotes Food and Drug Administration.

† A short course (usually 4 or 5 days) of some broad-spectrum cephalosporins appears to have efficacy similar to that of a 10-day course of penicillin, and a 5-day course of cefpodoxime
or cefdinir has been approved by the FDA for this indication.34 However, these agents are not recommended under most circumstances because they are more expensive and have an
unnecessarily broad spectrum as compared with penicillin or first-generation cephalosporins.
‡ Erythromycin has been a standard choice for patients who are allergic to penicillin; however, alternative agents have become more popular in recent years because of reduced gastroin-
testinal side effects and simpler dosing regimens.

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 clinical pr actice

associated with penicillin from the 1970s to the date, and absence of cough). The guidelines of the
1990s. A proposed explanation for the varying ACP, the AAFP, and the CDC endorse three alter­
rates of bacteriologic cure associated with penicil­native strategies for adults with two or more of the
lin treatment is the variation in the proportion of clinical criteria described above. The first strategy
S. pyogenes carriers in the study populations.44,45 is to treat patients with a positive rapid antigen-
Penicillin is less effective than cephalosporins or detection test. The second strategy is to treat pa­
clindamycin in eradicating asymptomatic carriage tients who meet all four clinical criteria without
of S. pyogenes. Accordingly, inclusion of a larger further testing and those who meet two or three
proportion of carriers in a trial would result in a clinical criteria and have a positive rapid antigen-
lower bacteriologic cure rate. In one randomized detection test. The third strategy is to test no one
trial comparing cefadroxil with penicillin in chil­ and to treat patients who meet three or four clin­
dren with a positive throat culture or rapid anti­ ical criteria. The IDSA and AHA do not endorse
gen-detection test, overall rates of bacteriologic the second and third strategies of the ACP, the
cure were 94% and 86%, respectively (P<0.01).40 AAFP, and the CDC because these approaches re­
However, among patients classified clinically (be­ sult in higher rates of prescribing unnecessary
fore analysis of the bacteriologic results) as likely
antibiotics.
to have streptococcal pharyngitis (i.e., those with All guidelines recommend penicillin orally or
tender cervical lymphadenopathy, tonsillar exudate, intramuscularly as the preferred therapy for strep­
or tonsillar petechiae and no cough, nasal con­ tococcal pharyngitis. The more recently published
gestion, or diarrhea), there was no significant dif­AHA guidelines also endorse once-daily amoxicil­
ference in cure rates between the two treatment lin as first-line therapy. The ACP, the AAFP, the
regimens. In contrast, among patients who were CDC, and the IDSA recommend the use of eryth­
classified clinically as probable carriers, the rateromycin in patients who are allergic to penicillin.
of bacteriologic cure was 95% in the cefadroxil The AHA recommends a first-generation cepha­
group and only 73% in the penicillin group. losporin in patients with penicillin allergy who
Several explanations have been proposed for the do not have immediate hypersensitivity to beta-
occasional failure of penicillin treatment, but datalactam antibiotics, with clindamycin, azithromy­
are lacking to provide support for them. Potential cin, or clarithromycin as an alternative treatment
mechanisms include local degradation of penicil­ option. Guidelines in some European countries
lin by beta-lactamases produced by other throat are largely consistent with these approaches,
flora and the inhibitory effect of penicillin on com­
whereas other European guidelines consider strep­
peting flora. However, data in support of either tococcal pharyngitis to be a self-limited illness
mechanism are not conclusive.40 There is no evi­ that does not require a specific diagnosis or anti­
dence that S. pyogenes has become more resistant biotic treatment except in high-risk patients (i.e.,
to penicillin. those with a history of acute rheumatic fever or
rheumatic heart disease) or severely ill patients.28
Guidel ine s In contrast, guidelines from India, where the in­
cidence of acute rheumatic fever remains high, list
Recommendations for the evaluation and treat­ intramuscular benzathine penicillin G first among
ment of streptococcal pharyngitis have been pub­ recommended therapies for streptococcal pharyn­
lished or endorsed by the American College of gitis.50
Physicians (ACP), the American Academy of Fam­
ily Physicians (AAFP), and the Centers for Disease C onclusions a nd
Control and Prevention (CDC)46,47; the Infectious R ec om mendat ions
Diseases Society of America (IDSA)48; and the
American Heart Association–American Academy In patients with symptoms and signs suggestive
of Pediatrics (AHA).49 All these guidelines con­ of streptococcal pharyngitis, such as the patient
sider it reasonable not to perform a throat culture in the vignette, a specific diagnosis should be
or rapid antigen-detection test in persons who determined by performing a throat culture or a
have none of the clinical features suggestive of rapid antigen-detection test with a throat culture
streptococcal infection (fever, tender cervical ad­ if the rapid antigen-detection test is negative, at
enopathy, tonsillar or pharyngeal swelling or exu­ least in children. Penicillin is the preferred treat­

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Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

ment, and a first-generation cephalosporin is an
acceptable alternative unless there is a history of
immediate hypersensitivity to a beta-lactam anti­
biotic. In the patient in the case vignette, the pos­
itive rapid antigen-detection test establishes a
diagnosis of streptococcal infection. I would rec­
ommend ibuprofen or acetaminophen for symp­
tomatic relief and would prescribe oral penicillin V
for 10 days. Since the rapid antigen-detection test
is positive, a throat culture is not needed for diag­
nosis, nor is one necessary after treatment, if symp­
toms resolve.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.

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